Calcium channel blockers are a heterogeneous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels. (Remington, The Science and Practice of pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p. 963 (1995)). The regulation of calcium entry into the cells of the cardiovascular system is of paramount importance to the proper functioning of this system. Cardiac and vascular smooth muscle cells have calcium channels located within the cell membrane. Calcium influx through these channels initiates a process of electromechanical coupling which ultimately leads to muscle contraction. The ability to regulate the entry of calcium into cardiac and vascular smooth muscle cells is a powerful therapeutic approach in the treatment of angina and hypertension. Likewise, blocking calcium influx into cardiac tissues and conduction systems can provide a useful approach for controlling certain types of arrhythmia.
The dihydropyridine calcium channel blocker, nisoldipine, is a yellow crystalline substance, which is practically insoluble in water, but soluble in ethanol. Nisoldipine coat-core (marketed as SULAR® by Sciele Pharma, Inc.) is a long-acting formulation of the drug, suitable for once daily administration in the treatment of patients with hypertension. SULAR® is an FDA approved controlled-release formulation of the calcium channel blocker, nisoldipine, which employs coat-core technology, and has been marketed for the treatment of hypertension since 1995. SULAR® tablets consist of an external coating and an internal core. Both the coating and the core contain nisoldipine; the coating as a slow release formulation and the core as an immediate or fast release formulation. In clinical trials in patients with mild to moderate hypertension, SULAR® has shown efficacy and tolerability similar to that of other calcium antagonists, and antihypertensive efficacy equivalent to that of agents from various other drug classes including beta-blockers, thiazide diuretics and ACE inhibitors. SULAR® demonstrates dose proportional pharmacokinetics and has a plasma half-life of about 7-12 hours with a mean Tmax of about 6-12 hours. The absolute bioavailability of nisoldipine from SULAR® is about 5%.
Unlike beta-blockers and thiazide diuretics, calcium antagonists (including nisoldipine coat-core) are not associated with clinically significant adverse metabolic effects on the serum lipid profile or glycaemic control. Nisoldipine coat-core maintains consistent plasma drug concentrations and antihypertensive effects throughout the 24-hour dosage interval, thereby attenuating intermittent reflex increases in sympathetic activity. In addition, the high degree of vasoselectivity of nisoldipine minimizes negative inotropic effects which may be observed with less selective agents such as nifedipine (Plosker, D L and Faulds, D. Drugs, 52(2), 232-53 (1996)).
Although the coat-core technology has been shown to be safe for the delivery of calcium channel blockers, studies have shown that there are slightly more adverse effects with the coat-core systems compared to other drug delivery systems, especially with respect to the drug, nifedipine (Defina et al. Ann Pharmacother. 31 (7-8): 819-822 (1997)). The coat-core technology also requires the use of specialized equipment which can be costly.
There exists a need for controlled release formulations that provides a lower dose of the drug, which may decrease the cost of manufacturing and may eliminate or diminish unwanted side effects, and which can be manufactured using conventional equipment.
Therefore, it is an object of the invention to provide controlled release formulations and methods of making and using thereof that provide alternative pharmacokinetic release profiles that may eliminate or diminish unwanted side effects and which are easier and cheaper to manufacture.
It is further an object of the invention to provide a controlled release formulation of a calcium channel blocker, such as nisoldipine, which is effective in the treatment of cardiovascular disorders, especially, hypertension, and which provides advantages over known formulations such as SULAR®.
It is further an object of the invention to provide a controlled release formulation of a calcium channel blocker, where the amount of the drug is efficacious, yet reduced, as compared to known formulations such as SULAR®.
It is yet another object of the invention to provide a controlled release formulation of a calcium channel blocker, where the bioavailability of the drug is increased compared to the bioavailability of the drug to known formulations such as SULAR®.